Repository vegetable oil, ethyl cellulose, tetracycline-type antibiotic composition



REPUSITORY VEGETABLE 011.33 CELLU LOSE, TETRACYCLiNE-TYPE ANTIBIGTIGCOM- POSITIUN Wilbur Ryder Burst; West Liifayetteglndg assign'or toAmerican Cyanamid- Company, New York, N. -Y., a corporation-'05 MaineNo'fiiawingr Applicatiou'llune 22,1955, Serial- No. 517,383

sciaims. outta-say This invention' relates' to a: repositorybase'-suitable'- as a liquid 1 carrier" for antibiotics for parenteralinjections, as well 'as'topical application, and'ra/metho'd Qfpreparingthe same. This application is a continuation'r-in-part of applicationSerial No. l68}663; filed June 16, 1950, now abandoned.v

The intramuscular route is preferred for the administration of manytherapeutic agents. Desirably-the rateof release of the agent iscontrolled. A patent to Welch, 2,491,537, Liquid InjectableOil-Pectin-Drug Therapeutic Compositions, describes certain advantagesof a delayed release. A- patent to Libby, 2,449,039, TherapeuticComposition, 'teaches the'suspensiorr of penicillin particles in'digestible glycerides, such as cornoil, and mentions ethyl cellulose asamong agents that may be present.

It has now been found that by heating ethyl cellulose in a vegetableoil, within th'e range" of 1 80 to 205 0., cooling, and suspending atherapeutic agent such as one of the tetracyclines in the thickened oil,an excellent repository base is obtained.

Myfnew repository base is sufiiciently thick as to elimimate thesettling outof powdered drug suspensions; is easy to'use, is convenientto prepare, readily permits'the formation'of a uniform suspension, andprovides-an anhydrous repository base particularly suitable forwater-sensitive drugs; Additionally, it is chemicallyinert,non-freezing, has but slight change in viscosity with'tempenature, andis usable over a wide temperature range.

Methocel, that is'methyl cellulose, hydroxy-ethyl-cellulose andcarboxy-methyl-cellulosedo not dissolve in the oil but decompose.Ethocel alone is soluble. By dissolving up to 5% of ethocel in avegetable oil such as corn oil at a temperature within" the range: ofapproximately 180 to 205 C., preferably within the. range1of195 to 200C., there is formed a smooth viscous oil in which the medicament may bedissolved or'suspen'ded. If temperatures of much above 205 C. are used,theoil-'ethocel mix darkens. If a temperature much below 180 C. is used,the ethocel'does not completely dissolve and'the product tends to bestringy and may contain bubbles; Of course, a longer period at asomewhat lower temperature may be used. The ethyl-cellulose used may. beesterified to a greater'or lesser degree, which, of course, affects theviscosity characteristics of the product.

The grade of ethyl-cellulose known as 100 centipoise is verysatisfactory for my purpose. (Note Henry A. Gardner, Examination ofPaints, or A. S. T. M. specifications on viscosity.) With the lowerviscosity ethers, more ethyl-cellulose may be dissolved. With the 100cp. product, approximately 5% of ethyl-cellulose will causethe mix togel to a solid mix which is thixotropic which, of course, is highlyadvantageous for the preparation of an injectable repository base.

My'product' may be used as a repository base for drugs which are solublein it or for drugs which are suspendable in it. In the base, drugsnormally have a longer period of therapeutic effectiveness than the samedrug injected in water. The period of therapeutic activity may icebevadditionally zprolongedabydissolving: epinephrineiin the mix.-Theidrugtmay betsuspended ins-the repository base after ithascooleditota sufiiciently low temperature as not to be damagingttotheadrugr: Prooaine: penicillin, for instance, is damaged ifiheatedabove about 56 C. For exceptionally stable drugs, it may, of course, bemixed while-'hot'l Among the -many-drugs-that-may be used areepinephrine, benzestrol; novocaine; d-tubocurarine, digitalis; alkali-salts of penicilli'n, amine salts of penicillin suchas'- procainepenicillin; cyclohexylguanylurea salts ofpenicillin chlortetracycline,tetracycline, bromotetracycline and theirsalts, such as thehydrochlorides, sulfates, on calcium salt' and' mixtures of suchproducts; Corn oil-"is-very satisfactory but'other'vegetable lOilS su'chas-peanut oilg sesame-oil, rape seed oil, poppy seed oil, and'cott'onseed-oil all form excellent injection bases.

The repository base is not subject to freezing nor separation understorage conditions. Its viscosity is substantially: constant over normalworking" ranges, including freezing weather: It'ischemically"unreactiveunder all normal conditions:

Tocopherolimaybe added to aid stability; The glyceride oils mayoxidiZeslowly; and" an antioxidant such as tocopherol or butylated'hydroxyanisol gives'addedtirne stability. Compound-F, h'ydiocorti'sonealcohol, may be added"to'reduce inflammatiorr.

The *gelled base containin'gthe' antibiotics also may be used"topically; including"treatmentof'ophthalmic conditions, or may beinjected into an' anirnals udder' as a mastitis treatment. Thecomparatively slight change in viscosity with temperature of this basemakes the preparation particularly effective for use as-a mastitis.ointment-in cold weather.

As examples oflcert'ain types of "drugs. and conditions, but not by wayoflirnitation,,.the followingexamples are given. 4

Example 1.

A repository ba'se'm'ixturewas preparedirom cc. of cornoil'and'l gram'of ethyl'cellulose,100"cp., by mixing, then heated'with' stirringto C.Themixture' was stirred until clear and bubble-free,.and cooled. Afterco'oling, .300000"units of crystalline procaine penicillin'G and100,000units of crystalline potassium peni: cillin G were madeup toa.volume. of 1" cc. with the base, all under sterile-conditions, themixture stirred until. uniforrnl'y suspended, and' the. penicillin. intherepository base was injected intothe hip muscle. Theproduct' waseasily syringahleiand exhibited no untowards effects in .the recipientand gavea comparatively stablelasting penicillin blood level.

Example- 2 A mixture was prepared containing lOOIcc. of'corn oil and215. grams of ethyl cellulose, 100 cp., the mixture heated'with stirringto200 C; untilthe mixture was clear and'b'ubble-free. Twenty grams ofclil'ortetracycline hydrochloride, micronized, were. suspended' in. themixture afterithad-cooled, and the product used for intramuscularinjection. The product is. stable and. syringable.

Example 3 A mixture wasrprepared of 100 cc. of corn-oil, 5 grams ofethyl cellulose, 100. cpugrade, the mixture stirred-and heated toatemperature of 200 C. uutilclear and bubblefree. The mixture.w-ascooled, thereby obtaining a clear solidified -gelwhichr on.shakingbecame. a. thick fluid. To 1 cc. of-the mixture wasaclded 15milligrams ofmicronized sterile. chlortetracyclinehydrochloride? and themixture found: satisfactory: for injection;

Example 4 A mixture was prepared containing 100 grams of sesame oil, 5grams of ethyl cellulose, 25 cp. grade, the mixture stirred with heatingto a temperature of 200 C. until clear and bubble-free. The mixture wascooled and thereto added grams of chlortetracycline as the free base. Asuspension was obtained suitable for injection.

Example 5 A mixture of 100 cc. rape seed oil and 2 /2 grams of 100 cp.grade ethyl cellulose was heated to 195 C. and stirred until clear andbubble-free. The mixture was allowed to cool to about 40 C. and theretoadded sufiicient procaine penicillin G and sodium penicillin G that theresultant mixture contained 300,000 units per cc. of procaine penicillinG and 100,000 units per cc. of sodium penicillin G, under sterileconditions. After mixing and cooling to room temperature, there resulteda viscous injectable material which was easily syringable, was stable,and maintained its potency for a long period.

Example 6 A mixture of 100 cc. cotton seed oil and 2 /2 grams of 100 cp.grade ethyl cellulose was heated to 200 C. and stirred until clear andbubble-free. The mixture was al lowed to cool to about 40 C. and theretoadded suificient procaine penicillin G and sodium penicillin G that theresultant mixture contained 300,000 units per cc. of procaine penicillinG and 100,000 units per cc. of sodium penicillin G. After mixing andcooling to room temperature, there resulted a viscous injectablematerial which was easily syringable, was stable, and maintained itspotency for a long period.

Example 7 To 100 cc. of corn oil was added 2.5 grams of ethyl cellulose,100 cp. grade, and the mixture heated with stirring at 200 C. untilclear and bubble-free. The mixture was cooled and to the gel atapproximately room temperature was added sulficient procaine penicillinG and sutficient sodium penicillin G that the resultant mixturecontained 300,000 units per cc. of procaine penicillin G and 100,000units per cc. of sodium penicillin G.

Mixtures of the same therapeutic agents in water and in peanut oil atthe same concentrations were prepared and rabbits injected therewith ata dosage level of 0.1 cc. per kilogram. After 48 hours, under strictlycomparable conditions, it was found that the rabbits which had beeninjected with the penicillin in the base prepared in accordance withExample 4 had an average blood level of 0.030 unit, whereas thoseinjected with the penicillin in each of Water and peanut oil gave anaverage of 0.006, both of which values are so low as to be totallyinadequate and barely suificient to show on assay. Indeed, most rabbitsgave no blood levels and others only a trace.

Example 8 120 grants of ethyl cellulose, 100 cp. grade, were dissolvedin 6,000 cc. of sesame oil by heating to 190 C. The hot solution wasstrained through 4 layers of cheesecloth, then cooled. To the cooledsolution were added 9 grams of mixed tocopherols and the mixturestirred.

To one-half of the oil was added 33 grams of tetracycline hydrochlorideand the oil run through a homogenizing mill. The preparation could beused topically, or intramuscularly.

Example 9 To 24,000 cc. of sesame oil were added 500 grams of ethylcllulose and the mixture heated at 190 C. until the ethyl cellulose haddissolved. The hot solution was strained through 4 layers of cheeseclothand cooled. To the cool solution were added sterilely 50 grams ofcommercial (34%) tocopherol, 375 grams of Compound F (hydrocortisonealcohol), and 250 grams of chlortetracycline hydrochloride. The mixturewas diluted to 24,-

4 700 cc. with sesame oil and the composition passed through an ointmentmill to disperse and blend the ingredients.

This composition is particularly useful as an eye ointment because theCompound F markedly decreases inflammation. The tocopherols add to thestability of the sesame oil, even though without them the composition iscomparatively stable.

Example 10 1,000 cc. of sesame oil were heated to 180 C. and theretoadded slowly with stirring 10 grams of ethyl cellulose. When dissolvedthe mixture was filtered through 6 layers of cheesecloth. The mixturewas cooled, /2 gram of Tenox II (butylated hydroxyanisol and citricacid) added as an antioxidant. 50 grams of chlortetracyclinehydrochloride were added and the mixture under sterile conditions waspassed through a colloid mill. The resulting preparation was used forthe treatment of psittacosis in parakeets. A single injection of thispreparation gave an adequate blood level of chlortetracycline in thebirds @for 3 days.

Example 11 Example 10 was repeated using tetracycline hydrochloride asthe antibiotic. The preparation on injection intramuscularly gave anadequate blood level in parakeets for 3 days.

Example 12 A composition was prepared containing 5% of tetracyclinehydrochloride in sesame oil without the ethylcellulose. When injectedunder comparable conditions, due provisions being taken to insure thatthe antibiotic remainded suspended in the oil, it was found that theblood level in the parakeets had dropped below a useful level in lessthan 24 hours.

Example 13 To a 1% ethyl cellulose in sesame oil base prepared as inExample 10, was added per milliliter, 100 milligrams ofchlortetracycline hydrochloride and 100 milligrams of neomycin sulfate.This preparation gave a stable composition, with a workable viscositysuitable for bovine mastitis treatment over a wide temperature range. Itwas particularly advantageous in cold weather as the material could beused immediately for treatment, whereas the older petrolattun basedointments required warming to reduce the viscosity before injection.

Example 14 Procedure of Example 4 was repeated using tetracycline as thefree base. The suspension obtained was suitable for injection.

Wide variations in the quantity of ethyl cellulose may be used,depending upon the viscosity of the product desired and the viscositygrade of the ethyl cellulose. The concentration of the drug used in thebase may vary within wide limits, being determined by convenience forthe user.

"I claim:

1. An anhydrous sterile repository composition comprising a vegetableoil, ethyl cellulose, and an antibiotic selected from the groupconsisting of chlortetracycline, tetracycline, bromotetracycline, andtheir acid and basic salts, said ethyl cellulose having been dissolvedin said vegetable oil at a temperature in the range of l-205 C. so as toform a viscous gel in said vegetable oil.

2. The composition of claim 1 in which the antibiotic ischlortetracycline hydrochloride.

3. The composition of claim 1 in which the antibiotic is tetracyclinehydrochloride.

4. The composition of claim 1 in which the antibiotic ischlortetracycline as the free base.

5. The composition of claim 1 in which the antibiotic is tetracycline asthe free base.

(References on following page) 5 6 1 References Cited in the file ofthis patent FOREIGN PATENTS UNITED STATES PATENTS 76,31'1' Sweden June10, 1931 1,963,901 Hickman June 19, 1934 OTHER REFERENCES 2,449,039Libby SePt- 7, 1948 5 Am Prof Pharm April 1941 225-227 1 pages 2,491,537Welch 20, 1949 Am. Prof. 1Pha'rm., May 1941, pages 296-297.

2,507,193 Buckwalter May 9, 1950

1. AN ANHYDROUS STERILE REPOSITORY COMPOSITION COMPRISING A VEGETABLEOIL, ETHYL CELLULOSE, AND AN ANTIBIOTIC SELECTED FROM THE GROUPCONSISTING OF CHLORTETRACYCLINE, TETRACYCLINE, BROMOTETRACYCLINE, ANDTHEIR ACID AND BASIC SALTS, SAID ETHYL CELLULOSE HAVING BEEN DISSOLVEDIN SAID VEGETABLE OIL AT A TEMPERATURE IN THE RANGE OF 180*-205* C. SOAS TO FORM A VISCOUS GEL IN SAID VEGETABLE OIL.